Successful stabilization of thermally labile biologicals requires a combination of appropriate formulations, a quick drying process with minimal thermal and mechanical stress, and solid state properties conducive to stable long term storage. Freeze drying and spray drying are two of the most widely used methods for drying API solutions in the pharmaceutical industry. Spray drying provides advantages of high volume product throughput (up to, e.g., 5,000 lb/hr) and reduced manufacturing times over batch process protein preservation/drying technologies, such as freeze drying. The challenge of using spray drying to stabilize thermally labile APIs, such as biopharmaceuticals, involves the control of four key areas: atomization conditions, drying conditions, formulation design, and resultant solid state properties of the dried materials. For example, during atomization, the process of breaking up a liquid stream into fine droplet sizes can involve excessive shear stress, surface tension, and pressure applied to the product, resulting in excessive loss of bioactivity. Additionally, some liquids exhibit high viscosity and density, which requires higher atomization pressure resulting in overly broad droplet size distribution.
Most ultrasonic spray devices and techniques are directed to spraying liquids to form uniform layers on surfaces or to provide high pressure sprays for fuel combustion. See, e.g., U.S. Pat. No. 4,978,067, Unitary Axial Flow Tube Ultrasonic Atomizer with Enhanced Sealing, or U.S. Pat. No. 4,541,564, Ultrasonic Liquid Atomizer, Particularly for High Volume Flow Rates, to Berger, et al. However the problems solved by these techniques are different from those in spray drying of pharmaceuticals. Ultrasonic spray drying of bioactive materials demands high droplet uniformity, quick drying and low stress not found in the prior art.
Conventional ultrasonic nozzles use a piezoelectric transducer to convert electrical energy to mechanical vibrations at ultrasonic frequency range (i.e. greater than 20 kHz). The ultrasonic vibrations are focused at the tip where, as the liquid flows through, the oscillating tip disintegrates the liquid into micro-droplets, and ejects them to form a gentle, low velocity spray of freely flowing formulations at ambient pressure (i.e., pressure-less) conditions. Because the main energy source controlling atomization is mechanical vibrations, the droplet size distribution of the atomized liquid is primarily a function of frequency, and the higher the frequency, the smaller the droplet diameter. However, typical median droplet size of aqueous fluids using these techniques is ˜90 microns at 20 kHz, and 45 microns at 40 kHz, which are still large for efficient, fast drying of the droplets to form dry stabilized powders. Another limitation is that the higher the frequency, the lower the processing capacity (i.e. flow rate).
In view of the above, a need exists for a method to spray thick pharmaceutical and vaccine formulations under low shear stress conditions. It would be desirable to be able to spray formulations with a wide range of solution concentrations under low pressures while providing small droplets of uniform size. The present invention provides these and other features that will be apparent upon review of the following.